Integrating Pharmacology and Microbial Network Analysis with Experimental Validation to Reveal the Mechanism of Composite Sophora Colon‐Soluble Capsule against Ulcerative Colitis

Abstract

Ulcerative colitis (UC) has multifactorial pathogenesis that acts synergistically, such as immune system dysregulation and expansion of infectious gut microbiota. Therefore, a multicomponent treatment derived from Chinese herbal medicine that interacts with multiple targets synergistically is needed. Composite sophora colon-soluble capsule (CSCC) is a Chinese herbal formula that has shown therapeutic efficacy against UC in randomized clinical trials. However, its bioactive components and potential target genes against UC remain unclear. Here, we used a network pharmacology approach to detect component-target-pathway interactions of CSCC against UC. A total of 29 gene targets, 91 bioactive components, and 20 enriched pathways of CSCC were identified. The IL-17 signaling pathway activated by infectious gastrointestinal microbes and predicted by the network analysis to be a major pathway modulated by CSCC against UC was studied in a dextran sulfate sodium-induced colitis model. CSCC showed remarkable efficacy against UC with respect to the attenuation of colon length, body weight loss, and disease activity index through gut microbiota recovery and intestinal immune homeostasis. The rectal administration of CSCC reduced the numbers of Th17 cells isolated from both mesenteric lymph nodes and lamina propria mononuclear cells and the levels of IL-17A, IL-6, IL-1β, and TNF-α. Additionally, the percentage of Treg cells and the levels of their hallmark cytokines were upregulated. Rectal administration of CSCC led to microbiota regulation with a significant correlation between suppression of Verrucomicrobiaceae and Ruminococcaceae, as well as the elevation of Lactobacillaceae, and CSCC administration via microbiome correlation heatmaps and cooccurrence network analysis at multiple time points. Thus, our study presents an effective herbal formula, CSCC, for UC treatment and explores its components and mechanisms of efficacy through the examination of gut microbiota and hallmark cytokines in the IL-17 pathway.

Efficacy and Safety of Sophora flavescens (Kushen) Based Traditional Chinese Medicine in the Treatment of Ulcerative Colitis: Clinical Evidence and Potential Mechanisms

“…Other experiments have shown that Kushen used in vivo can significantly reduce the number of invasive microbial populations in the intestines of mice, thereby lowering animal mortality caused by E. coli and Clostridium perfringens type B. Besides, Kushen was validated to inhibit NK-1R expression, leading to a reduced secretion of inflammatory cytokines such as IL-1β and IL-8 in cells and the promotion of IFN-γ synthesis ( Holleran et al, 2020 ; Ding et al, 2020 ). Consequently, this produces certain regulatory effects on abnormal immune responses in the intestinal mucosa.…”

“…Radix Sophorae flavescentis (Kushen) is a monarch herb in TCM formulations (Kushen-based TCM formulations) used for the treatment of UC with DHAS which has achieved good effectiveness in clinical practice and effect studies ( Tong et al, 2010 ; Tong et al, 2011 ; Gong et al, 2012 ; Fang et al, 2018 ; Chen et al, 2020 ). Kushen mainly contains the components matrine and oxymatrine , which are active ingredients against UC with significant inhibitory effects on invasive microbial populations such as Escherichia coli and Proteus mirabilis, as well as immunosuppressive effects against IL-1β and IL-17 in the intestinal epithelium ( Lin et al, 2019 ; Xu et al, 2019 ; Ding et al, 2020 ). Based on these findings, meta-analysis and network pharmacology approaches were conducted to examine the published efficacies of Kushen-based TCM formulations compared to 5-ASA in the treatment of UC, detect and identify potential pathways of Kushen against UC with DHAS, and provide evidence-based scientific support for UC treatment in clinical practice ( Figure 1 ).…”

Artemisinin Alleviates Intestinal Inflammation and Metabolic Disturbance in Ulcerative Colitis Rats Induced by DSS

“…IL-17 is a specific effector secreted by Th17 cells, which has a strong inflammatory effect. It promotes the production of IL-6, IL-1 β , and other inflammatory factors through recruitment, mobilization, and activation of macrophages and neutrophil granulocytes and mediates inflammatory invasion and tissue damage [ 28 ]. As a proinflammatory factor, IL-23 is involved in the formation and expansion of IL-17.…”

Exploring the Potential Mechanism of Guchang Zhixie Wan for Treating Ulcerative Colitis by Comprehensive Network Pharmacological Approaches and Molecular Docking Validation as Well as Cell Experiments

“…Eighteen male SD rats were randomly allocated into 3 groups: The blank group, the model group, and the treatment group with 6 rats in each group. The model group and the treatment group were induced by the administration of 3 % (w/v) dextran sulfate sodium (DSS; MP Biomedicals, USA) in distilled drinking water for 7 d, followed by distilled water for 7 d as previous described [64,65] . Rats in blank group were fed with distilled water for 14 days.…”

“…The model group and the treatment group were induced by the administration of 3 % (w/v) dextran sulfate sodium (DSS; MP Biomedicals, USA) in distilled drinking water for 7 d, followed by distilled water for 7 d as previous described. [64,65] Rats in blank group were fed with distilled water for 14 days. Dosages were calculated as previously described.…”